Recent studies have shown that the diaphragm, like limb muscles, fatigues when its workloads is excessive and that diaphragm fatigue, in turn, may produce hypercapneic respiratory failure in patients with lung disease. While the cause(s) of respiratory muscle fatigue are not entirely clear, it has been suggested that diaphragm function depends on the balance between blood flow and metabolic demand. Blood flow may influence the development of fatigue by determining the rate at which critical substrates are delivered to the diaphragm (i.e. oxygen, glucose, etc.) and the rate at which toxic metabolic byproducts are washed away. It is also possible that insufficient bloodflow may lead to free radical generation by the diaphragm. Free radicals may damage intracellular organelles involved in excitation contraction coupling, producing a long lasting form of fatigue. Finally, ischemia may lead to activation of afferent neural fibers in the diaphragm, altering efferent motor drive and muscle tension output. The goal of this proposal is to examine the direct (i.e. changes in diaphragm contractility) and indirect (i.e. reflex changes in motor drive) effects of alterations in blood flow on diaphragm force output. We plan to investigate (a) the effect alterations in diaphragm blood flow, produced by mechanically varying phrenic artery perfusion pressure, on the rate of development and recovery from diaphragmatic fatigue; we will also examine the mechanisms by which blood flow influences fatigue; (b) the effect of pharmacologic agents, i.e. vasoactive drugs and free radical scavengers, on the rate of development of diaphrogmatic fatigue, and (c) the reflex effects of diaphragmatic fatigue on respiratory motor drive. Studies will be performed using an in situ canine diaphragm muscle preparation that permits (a) continuous measurement of diaphragm tension, electromyographic activity, and blood flow, (b) mechanical adjustment of phrenic perfusion pressure to valves above or below systemic arterial pressure, and (c) direct infusion of pharmacologic agents or solutions into the diaphragm. We believe that these studies will provide useful information concerning the mechanism by which respiratory muscle fatigue develops. In addition, we may be able to identify pharmacologic approaches to increasing diaphragm endurance which, in turn, may lead to new strategies for treating patients with respiratory failure.